TY - JOUR
T1 - Deoxycholic Acid and Risks of Cardiovascular Events, ESKD, and Mortality in CKD
T2 - The CRIC Study
AU - Chronic Renal Insufficiency Cohort (CRIC) Study Investigators
AU - Frazier, Rebecca
AU - Cai, Xuan
AU - Lee, Jungwha
AU - Bundy, Joshua D.
AU - Jovanovich, Anna
AU - Chen, Jing
AU - Deo, Rajat
AU - Lash, James P.
AU - Anderson, Amanda Hyre
AU - Go, Alan S.
AU - Feldman, Harold I.
AU - Shafi, Tariq
AU - Rhee, Eugene P.
AU - Miyazaki, Makoto
AU - Chonchol, Michel
AU - Isakova, Tamara
N1 - Funding Information:
Funding for the CRIC Study was obtained from grants U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902 under a cooperative agreement from the NIDDK. In addition, this study was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award National Institutes of Health/National Center for Advancing Translational Sciences (UL1TR000003), the Johns Hopkins Institute for Clinical and Translational Research (UL1TR000424), University of Maryland General Clinical Research Center (M01RR-16500), Clinical and Translational Science Collaborative of Cleveland (UL1TR000439), Michigan Institute for Clinical and Health Research (UL1TR000433), University of Illinois at Chicago Clinical and Translational Science Awards (UL1RR029879), Tulane Center of Biomedical Research Excellence for Clinical and Translational Research in Cardiometabolic Diseases (P20GM109036), and Kaiser Permanente National Institutes of Health/National Center for Research Resources University of California San Francisco Clinical and Translational Science Institute (UL1RR024131).
Funding Information:
Dr Isakova reports consulting honorariums from Akebia Therapeutics, Inc, Kyowa Kirin Co, Ltd, and LifeSci Capital, LLC. Dr Feldman reports relationships with Kyowa Hakko Kirin Co, Ltd, American Journal of Kidney Disease, InMed Physicians, and DLA Piper LLP. Drs Anderson, Go, and Lash report grants from the NIH during the conduct of the study. Dr Go reports grants from AstraZeneca. The remaining authors declare that they have no relevant financial interests.
Funding Information:
This work was supported by the George M. O’Brien Kidney Research Center at Northwestern University (NU-GoKIDNEY; P30DK114857) from the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). RF was supported by grant T32DK108738 from the NIDDK. TI was supported by grants R01DK102438, R01DK110087, and U01DK099930 from the NIDDK and K24HL150235 from the National Heart, Lung, and Blood Institute.
Funding Information:
Lawrence J. Appel, MD, MPH, Harold I. Feldman, MD, MSCE, Alan S. Go, MD, Jiang He, MD, PhD, James P. Lash, MD, Robert G. Nelson, MD, PhD, MS, Mahboob Rahman, MD, Panduranga S. Rao, MD, Vallabh O. Shah, PhD, MS, Raymond R. Townsend, MD, and Mark L. Unruh, MD, MS. Rebecca Frazier, MD, Xuan Cai, MS, Jungwha Lee, PhD, Joshua D. Bundy, PhD, MPH, Anna Jovanovich, MD, Jing Chen, MD, MMSc, MSc, Rajat Deo, MD, MTR, James P. Lash, MD, Amanda Hyre Anderson, PhD, MPH, Alan S. Go, MD, Harold I. Feldman, MD, MSCE, Tariq Shafi, MBBS, MHS, Eugene P. Rhee, MD, Makoto Miyazaki, PhD, Michel Chonchol, MD, and Tamara Isakova, MD, MMSc, on behalf of the CRIC Study Investigators. Study design: TI, MC, MM, AJ; data collection: JPL, RD, AHA, JC, ASG, TS, HIF; data analysis: XC, JL, MM; data interpretation: TI, MC, AJ, ER, RF, JDB; figure creation: XC. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This work was supported by the George M. O'Brien Kidney Research Center at Northwestern University (NU-GoKIDNEY; P30DK114857) from the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). RF was supported by grant T32DK108738 from the NIDDK. TI was supported by grants R01DK102438, R01DK110087, and U01DK099930 from the NIDDK and K24HL150235 from the National Heart, Lung, and Blood Institute. Funding for the CRIC Study was obtained from grants U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902 under a cooperative agreement from the NIDDK. In addition, this study was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award National Institutes of Health/National Center for Advancing Translational Sciences (UL1TR000003), the Johns Hopkins Institute for Clinical and Translational Research (UL1TR000424), University of Maryland General Clinical Research Center (M01RR-16500), Clinical and Translational Science Collaborative of Cleveland (UL1TR000439), Michigan Institute for Clinical and Health Research (UL1TR000433), University of Illinois at Chicago Clinical and Translational Science Awards (UL1RR029879), Tulane Center of Biomedical Research Excellence for Clinical and Translational Research in Cardiometabolic Diseases (P20GM109036), and Kaiser Permanente National Institutes of Health/National Center for Research Resources University of California San Francisco Clinical and Translational Science Institute (UL1RR024131). The funders of this study did not have any role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. Dr Isakova reports consulting honorariums from Akebia Therapeutics, Inc, Kyowa Kirin Co, Ltd, and LifeSci Capital, LLC. Dr Feldman reports relationships with Kyowa Hakko Kirin Co, Ltd, American Journal of Kidney Disease, InMed Physicians, and DLA Piper LLP. Drs Anderson, Go, and Lash report grants from the NIH during the conduct of the study. Dr Go reports grants from AstraZeneca. The remaining authors declare that they have no relevant financial interests. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. Part of this work was presented as a poster presentation at the American Society of Nephrology Scientific Session on November 7, 2019 in Washington, DC. Received March 31, 2021. Evaluated by 2 external peer reviewers, with direct editorial input by the Statistical Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form September 26, 2021.
Publisher Copyright:
© 2021
PY - 2022/1
Y1 - 2022/1
N2 - Rationale & Objective: Elevated levels of deoxycholic acid (DCA) are associated with adverse outcomes and may contribute to vascular calcification in patients with chronic kidney disease (CKD). We tested the hypothesis that elevated levels of DCA were associated with increased risks of cardiovascular disease, CKD progression, and death in patients with CKD. Study Design: Prospective observational cohort study. Setting & Participants: We included 3,147 Chronic Renal Insufficiency Cohort study participants who had fasting DCA levels. The average age was 59 ± 11 years, 45.3% were women, 40.6% were African American, and the mean estimated glomerular filtration rate was 42.5 ± 16.0 mL/min/1.73 m2. Predictor: Fasting DCA levels in Chronic Renal Insufficiency Cohort study participants. Outcomes: Risks of atherosclerotic and heart failure events, end-stage kidney disease (ESKD), and all-cause mortality. Analytical Approach: We used Tobit regression to identify predictors of DCA levels. We used Cox regression to examine the association between fasting DCA levels and clinical outcomes. Results: The strongest predictors of elevated DCA levels in adjusted models were increased age and nonuse of statins. The associations between log-transformed DCA levels and clinical outcomes were nonlinear. After adjustment, DCA levels above the median were independently associated with higher risks of ESKD (HR, 2.67; 95% CI, 1.51-4.74) and all-cause mortality (HR, 2.13; 95% CI, 1.25-3.64). DCA levels above the median were not associated with atherosclerotic and heart failure events, and DCA levels below the median were not associated with clinical outcomes. Limitations: We were unable to measure DCA longitudinally or in urinary or fecal samples, and we were unable to measure other bile acids. We also could not measure many factors that affect DCA levels. Conclusions: In 3,147 participants with CKD stages 2-4, DCA levels above the median were independently associated with ESKD and all-cause mortality.
AB - Rationale & Objective: Elevated levels of deoxycholic acid (DCA) are associated with adverse outcomes and may contribute to vascular calcification in patients with chronic kidney disease (CKD). We tested the hypothesis that elevated levels of DCA were associated with increased risks of cardiovascular disease, CKD progression, and death in patients with CKD. Study Design: Prospective observational cohort study. Setting & Participants: We included 3,147 Chronic Renal Insufficiency Cohort study participants who had fasting DCA levels. The average age was 59 ± 11 years, 45.3% were women, 40.6% were African American, and the mean estimated glomerular filtration rate was 42.5 ± 16.0 mL/min/1.73 m2. Predictor: Fasting DCA levels in Chronic Renal Insufficiency Cohort study participants. Outcomes: Risks of atherosclerotic and heart failure events, end-stage kidney disease (ESKD), and all-cause mortality. Analytical Approach: We used Tobit regression to identify predictors of DCA levels. We used Cox regression to examine the association between fasting DCA levels and clinical outcomes. Results: The strongest predictors of elevated DCA levels in adjusted models were increased age and nonuse of statins. The associations between log-transformed DCA levels and clinical outcomes were nonlinear. After adjustment, DCA levels above the median were independently associated with higher risks of ESKD (HR, 2.67; 95% CI, 1.51-4.74) and all-cause mortality (HR, 2.13; 95% CI, 1.25-3.64). DCA levels above the median were not associated with atherosclerotic and heart failure events, and DCA levels below the median were not associated with clinical outcomes. Limitations: We were unable to measure DCA longitudinally or in urinary or fecal samples, and we were unable to measure other bile acids. We also could not measure many factors that affect DCA levels. Conclusions: In 3,147 participants with CKD stages 2-4, DCA levels above the median were independently associated with ESKD and all-cause mortality.
KW - Cardiovascular disease
KW - chronic kidney disease
KW - deoxycholic acid
KW - end-stage kidney disease
KW - mortality
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UR - http://www.scopus.com/inward/citedby.url?scp=85122705375&partnerID=8YFLogxK
U2 - 10.1016/j.xkme.2021.09.004
DO - 10.1016/j.xkme.2021.09.004
M3 - Article
AN - SCOPUS:85122705375
VL - 4
JO - Kidney Medicine
JF - Kidney Medicine
SN - 2590-0595
IS - 1
M1 - 100387
ER -